Intrinsic aerobic capacity sets a divide for aging and longevity

Abstract

Rationale: Low aerobic exercise capacity is a powerful predictor of premature morbidity and mortality for healthy adults as well as those with cardiovascular disease. For aged populations, poor performance on treadmill or extended walking tests indicates closer proximity to future health declines. Together, these findings suggest a fundamental connection between aerobic capacity and longevity.

Objectives: Through artificial selective breeding, we developed an animal model system to prospectively test the association between aerobic exercise capacity and survivability (aerobic hypothesis).

Methods and results: Laboratory rats of widely diverse genetic backgrounds (N:NIH stock) were selectively bred for low or high intrinsic (inborn) treadmill running capacity. Cohorts of male and female rats from generations 14, 15, and 17 of selection were followed for survivability and assessed for age-related declines in cardiovascular fitness including maximal oxygen uptake (VO(2max)), myocardial function, endurance performance, and change in body mass. Median lifespan for low exercise capacity rats was 28% to 45% shorter than high capacity rats (hazard ratio, 0.06; P<0.001). VO(2max), measured across adulthood was a reliable predictor of lifespan (P<0.001). During progression from adult to old age, left ventricular myocardial and cardiomyocyte morphology, contractility, and intracellular Ca(2+) handling in both systole and diastole, as well as mean blood pressure, were more compromised in rats bred for low aerobic capacity. Physical activity levels, energy expenditure (Vo(2)), and lean body mass were all better sustained with age in rats bred for high aerobic capacity.

Conclusions: These data obtained from a contrasting heterogeneous model system provide strong evidence that genetic segregation for aerobic exercise capacity can be linked with longevity and are useful for deeper mechanistic exploration of aging.

Figure 1. A prospective test of the “aerobic hypothesis” in rats selectively bred to contrast for intrinsic endurance exercise capacity

Data collected in Trondheim, Norway. (A) Survival curves are significantly different between Low Capacity Runners (LCR; n = 23) and High Capacity Runners (HCR: n = 23). Logrank test; (P<0.0001). (B-E) Maximal oxygen consumption (VO_2max) assessed longitudinally at 15, 20, 25, and 34 months of age predicted lifespan both between and within selected lines. (F) PGC-1α and UCP2 in left ventricular tissue. (G) Total antioxidant status in plasma (TAS).

Figure 2. Properties of cardiac ventricular cardiomyocytes were more compromised as a function of age in LCR compared with HCR rats

(A&B) Cell length and width increased in old LCR but not in old HCR. (C) Isolated cell shortening greater in HCR than LCR in both adult and old age (D) Amplitude of Ca²⁺ transients decreased with aging in LCR but not HCR. (E) Example signals of Ca2+ transients. (F) Sarcoplasmic reticulum Ca²⁺ load measured after caffeine application was reduced in LCR vs. HCR cells, and deteriorated with aging in LCR, but not HCR cells. Adult: 15-20 months; Old Age: >25 months. *: p<0.05 age-matched LCR vs. HCR.

Figure 3. Diastolic properties of cardiac ventricular cardiomyocytes were more compromised in adult LCR compared with HCR rats, and this difference was sustained or accentuated with aging

(A&B) Cell relaxation and rate of Ca²⁺ transient decay were impaired in LCR rats compared to HCR rats, but did not change with aging. (C) Diastolic Ca²⁺ concentration was higher in adult LCR rats compared to adult HCR, and increased with aging in LCR, but not HCR rats. Adult: 15-20 months; Old Age: >25 months. *: p<0.05 age-matched LCR vs. HCR.

Figure 4. Sarcoplasmic reticulum Ca²⁺ leak was more compromised in LCR rats compared with HCR rats, and this difference was sustained with aging

(A) Example confocal images of Ca²⁺ sparks from quiescent cells. (B-E) Ca²⁺ spark frequency, amplitude, and width and duration at half-maximum amplitude were higher in LCR than HCR rats, indicating increased loss of sarcoplasmic reticulum Ca²⁺. (F&G) Quantitative assessments of sarcoplasmic reticulum Ca²⁺ leak confirmed that cells of old LCR rats had greater Ca²⁺ leak than HCR equivalents. Adult: 15-20 months; Old Age: >25 months. *: p<0.05 age-matched LCR vs. HCR.

Figure 5. Evidence to suggest mild pathological remodelling in LCR over HCR rats

(A) Transverse (T) tubule density relative to cardiomyocyte cell size decreased in old LCR but not old HCR rats. (B) Representative examples of cardiomyocytes stained with Di-8-ANEPPS for imaging of T-tubules in old LCR and HCR rats. (C) Higher systolic and (D) diastolic blood pressures in the LCR vs. HCR might be responsible for part of the cardiac cellular changes. *: p<0.05 age-matched LCR vs. HCR. (E) Light micrographs (hematoxylin and eosin stained) of myocardium from representative HCR (left) and LCR (right, both old age). Vacuolization marked with arrows and interstitial fibroplasia marked by letter F. Bar = 50 μm.

Figure 6. Survival features in LCR and HCR rats support intrinsic aerobic capacity as a biomarker of aging

(A-B) Survival curves for rats aged at the University of Michigan, Ann Arbor confirmed that HCR (n= 53) live longer than LCR (n=40). Logrank test; (P<0.0001). (C-E) Treadmill running distances at 3, 14, and 21 months of age were statistical predictors of age at death in HCR but not LCR rats. (F&G) Gains in body weight between 3 and 14 months of age associated with a decrease in survival in both females and males. Linear regressions are shown with 95% confidence intervals.